Rare corneal clones in mice suggest an age-related decrease of stem cell activity and support the limbal epithelial stem cell hypothesis

Douvaras, Panagiotis; Webb, Shaun; Whitaker, Duncan Andrew.; Dora, Natalie; Hill, Robert E.; Dorin, Julia R.; West, John D.

doi:10.1016/j.scr.2011.08.007

Cited by 24 publications

(27 citation statements)

References 28 publications

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“…The authors reasoned that if LESCs were active during normal homeostasis, as the LESC proposes, the donor limbal tissue should colonise the cornea without being stimulated to do so by wounding. However, others have pointed out that the CESC hypothesis is not consistent with some of the earlier experimental evidence [16][17][18] .…”

Section: Corneal Epithelial Stem Cell Hypothesismentioning

confidence: 72%

“…Stripe 1 also appears to be radially aligned with other β-gal-stained tissue located more centrally so it may be a longer discontinuous stripe. Discontinuous stripes have been discussed elsewhere for KRT5 LacZ/-transgenic mosaics [17] and also occur in mouse chimaeras and X-inactivation mosaics [27,72,103] . The discontinuities in β-gal staining shown in Figure 6A could reflect: (1) separate clones of cells derived from β-gal-positive and β-gal-negative CESCs or TACs that are radially aligned; (2) dispersal of a β-gal-positive clones by incursions from laterally adjacent β-galnegative clones; or (3) alternating contributions of more than one stem cell to a single radial stripe if individual stem cells cycle through phases of activity and quiescence.…”

Section: Lineage Tracing Experimentsmentioning

confidence: 91%

“…Observations on KRT5-LacZ +/-transgenic mice showed that they had rare β-gal-positive stripes in a predominantly β-gal-negative corneal epithelium, so largely avoiding the problem of multiple adjacent clones [17] . The distribution of β-gal-positive stripes was not consistent with predictions of centrifugal extension of clones of labelled cells from β-gal-positive CESCs distributed randomly in the corneal epithelium and the simplest interpretation is that the stripes represent clonal lineages derived from LESCs located in the limbus.…”

Section: Change In Mosaic Patterns After Birthmentioning

confidence: 99%

“…Stripe 1 has its peripheral end in the limbus and its more central end in the cornea so, using the stripe classification system described for mosaic KRT5 LacZ/-transgenic mice [17] , it is classified as a limbus-cornea (LC) stripe. This is consistent with expectations of the LESC hypothesis (Time 2 in Figure 5A), particularly as the stripe does seem to extend into the limbus itself (arrow in Figure 6A).…”

Section: Lineage Tracing Experimentsmentioning

confidence: 99%

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Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

West¹,

Dora²,

Collinson

2015

WJSC

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In this review we evaluate evidence for three different hypotheses that explain how the corneal epithelium is maintained. The limbal epithelial stem cell (LESC) hypothesis is most widely accepted. This proposes that stem cells in the basal layer of the limbal epithelium, at the periphery of the cornea, maintain themselves and also produce transient (or transit) amplifying cells (TACs). TACs then move centripetally to the centre of the cornea in the basal layer of the corneal epithelium and also replenish cells in the overlying suprabasal layers. The LESCs maintain the corneal epithelium during normal homeostasis and become more active to repair significant wounds. Second, the corneal epithelial stem cell (CESC) hypothesis postulates that, during normal homeostasis, stem cells distributed throughout the basal corneal epithelium, maintain the tissue. According to this hypothesis, LESCs are present in the limbus but are only active during wound healing. We also consider a third possibility, that the corneal epithelium is maintained during normal homeostasis by proliferation of basal corneal epithelial cells without any input from stem cells. After reviewing the published evidence, we conclude that the LESC and CESC hypotheses are consistent with more of the evidence than the third hypothesis, so we do not consider this further. The LESC and CESC hypotheses each have difficulty accounting for one main type of evidence so we evaluate the two key lines of evidence that discriminate between them. Finally, we discuss how lineage-tracing experiments have begun to resolve the debate in favour of the LESC hypothesis. Nevertheless, it also seems likely that some basal corneal epithelial cells can act as long-term progenitors if limbal stem cell function is compromised. Thus, this aspect of the CESC hypothesis may have a lasting impact on our understanding of corneal epithelial maintenance, even if it is eventually shown that stem cells are restricted to the limbus as proposed by the LESC hypothesis.

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Section: Corneal Epithelial Stem Cell Hypothesismentioning

confidence: 72%

Section: Lineage Tracing Experimentsmentioning

confidence: 91%

Section: Change In Mosaic Patterns After Birthmentioning

confidence: 99%

Section: Lineage Tracing Experimentsmentioning

confidence: 99%

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Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

West¹,

Dora²,

Collinson

2015

WJSC

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“…Indirect evidence from analysis of coherent clonal lineages in adult mouse X-inactivation mosaics, transgenic mosaics and chimeras predicts that LESCs are also either numerically deficient and/or functionally defective in heterozygous Pax6 +/− mice [22] and older WT mice [24], [25], [26]. These mice exhibit radial stripes, which are thought to represent clonally related populations of corneal keratinocytes migrating from a LESC population at the periphery.…”

Section: Introductionmentioning

confidence: 99%

Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6+/− Mouse Model of Aniridia

et al. 2013

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We aimed to test previous predictions that limbal epithelial stem cells (LESCs) are quantitatively deficient or qualitatively defective in Pax6+/− mice and decline with age in wild-type (WT) mice. Consistent with previous studies, corneal epithelial stripe patterns coarsened with age in WT mosaics. Mosaic patterns were also coarser in Pax6+/− mosaics than WT at 15 weeks but not at 3 weeks, which excludes a developmental explanation and strengthens the prediction that Pax6+/− mice have a LESC-deficiency. To investigate how Pax6 genotype and age affected corneal homeostasis, we compared corneal epithelial cell turnover and label-retaining cells (LRCs; putative LESCs) in Pax6+/− and WT mice at 15 and 30 weeks. Limbal BrdU-LRC numbers were not reduced in the older WT mice, so this analysis failed to support the predicted age-related decline in slow-cycling LESC numbers in WT corneas. Similarly, limbal BrdU-LRC numbers were not reduced in Pax6+/− heterozygotes but BrdU-LRCs were also present in Pax6+/− corneas. It seems likely that Pax6+/− LRCs are not exclusively stem cells and some may be terminally differentiated CD31-positive blood vessel cells, which invade the Pax6+/− cornea. It was not, therefore, possible to use this approach to test the prediction that Pax6+/− corneas had fewer LESCs than WT. However, short-term BrdU labelling showed that basal to suprabasal movement (leading to cell loss) occurred more rapidly in Pax6+/− than WT mice. This implies that epithelial cell loss is higher in Pax6+/− mice. If increased corneal epithelial cell loss exceeds the cell production capacity it could cause corneal homeostasis to become unstable, resulting in progressive corneal deterioration. Although it remains unclear whether Pax6+/− mice have LESC-deficiency, we suggest that features of corneal deterioration, that are often taken as evidence of LESC-deficiency, might occur in the absence of stem cell deficiency if corneal homeostasis is destabilised by excessive cell loss.

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The vertebrate corneal epithelium: From early specification to constant renewal

Dhouailly¹,

Pearton

Michon

2014

Developmental Dynamics

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BACKGROUND:The cornea is an ectodermal/neural crest derivative formed through a cascade of molecular mechanisms to give rise to the specific optical features necessary for its refractory function. Moreover, during cornea formation and maturation, epithelial stem cells are sequestered to ensure a constant source for renewal in the adult. RESULTS: Recent progress in the molecular and stem cell biology of corneal morphogenesis and renewal shows that it can serves as a paradigm for epithelial /mesenchymal organ biology. This review will synthesize historical knowledge together with recent data to present a consistent overview of cornea specification, formation, maturation, and maintenance. CONCLUSIONS: This should be of interest not only to developmental biologists but also ophthalmologists, as several human vision problems are known to be rooted in defects in corneal development.

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Rare corneal clones in mice suggest an age-related decrease of stem cell activity and support the limbal epithelial stem cell hypothesis

Cited by 24 publications

References 28 publications

Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6+/− Mouse Model of Aniridia

The vertebrate corneal epithelium: From early specification to constant renewal

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